Overall effectiveness of pneumococcal conjugate vaccines: An economic analysis of PHiD-CV and PCV-13 in the immunization of infants in Italy

Figures & data

Table 1. Base-case analysis results (18-year time horizon).

	No vaccination	PCV-7	PCV-13	PHiD-CV
Effectiveness (undiscounted)
Cases of meningitis (n)	117	68	48	48
Cases of bacteremia (n)	207	119	83	83
Cases of pneumonia (n)	318,015	307,149	301,418	301,418
Cases of AOM (n)	1,576,211	1,507,479	1,361,368	1,341,226
Cases of (AOM) sequelae (n)	21	13	9	9
All deaths (n)	2,608	2,600	2,596	2,596
QALYs	8,092,626	8,093,201	8,094,029	8,094,129
LYs	8,903,903	8,904,035	8,904,086	8,904,086
Costs (undiscounted)
Vaccine (€)	—	NA	88,977,589	88,977,589
Acute meningitis (€)	943,520	546,103	387,134	387,134
Meningitis sequelae (€)	1,526,213	857,494	590,004	590,004
Bacteremia (€)	658,774	376,648	263,796	263,796
Pneumonia (€)	74,831,401	67,620,401	66,193,669	66,193,669
AOM (€)	73,431,910	69,410,537	60,862,579	59,684,201
Total (€)	151,391,817	NA	217,274,772	216,096,394
Summary discounted outcomes
QALYs	6,283,557	6,284,049	6,284,780	6,284,870
LYs	6,914,139	6,914,238	6,914,276	6,914,276
Total costs (€)	131,150,394	NA	197,804,453	196,735,985
ICER (€/QALY gained)
vs. no vaccination	—	—	54,501	49,957
vs. PCV-13	—	—	—	Dominant

* General + disease-specific mortality

AOM: Acute otitis media; ICER: Incremental cost-effectiveness ratio; LYs: Life years; PCV-7: 7-valent pneumococcal conjugate vaccine; PCV-13: 13-valent pneumococcal conjugate vaccine; PHiD-CV: Pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; QALYs: Quality-adjusted life years.

Figure 1. PSA: Scatterplot for PHiD-CV vs. PCV-13 (18-year time horizon). PSA: Probabilistic sensitivity analysis; PCV-13: 13-valent pneumococcal conjugate vaccine; PHiD-CV: Pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; QALY: Quality-adjusted life year.

Figure 2. DSA: Tornado diagram of ICER of PHiD-CV vs. PCV-13.

AOM: Acute otitis media; DSA: Deterministic sensitivity analysis; ICER: Incremental cost-effectiveness ratio; IPD: Invasive pneumococcal disease; PHiD-CV: Pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; PCV-13: 13-valent pneumococcal conjugate vaccine; VE: Vaccine effectiveness.

Figure 3. Model flow diagram. Rectangles represent mutually exclusive health states. Dotted rectangles represent absorbing health states and represent the proportion of the population removed from the model. Age-specific incidences are applied monthly to the susceptible population, after accounting for arm-specific VE. Costs and benefits are computed monthly and aggregated over the analyzed time horizon. Non-consulting AOM are accounted for in the quality-of-life impact calculation. No Vaccination: is a counterfactual scenario, in which universal vaccination is not fostered by the health system. It allows assessing the absolute value of PCV vaccination programs, and not only the comparison between 2 specific vaccination products.

AOM: Acute otitis media; PCV-7: 7-valent pneumococcal conjugate vaccine; PCV-13: 13-valent pneumococcal conjugate vaccine; PHiD-CV: Pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; Sp: Streptococcus pneumonia.

Table 2. Clinical inputs.

Epidemiological data
	Meningitis			Bacteremia		Hospitalized pneumonia			Non-hospitalized pneumonia		AOM
Age (years)	Incidence rate (x100,000)^Citation10	Case fatality ratio (%)^Citation35	Cases with sequelae (%)^Citation35	Incidence rate (x100,000)^Citation10	Case fatality ratio (%)^Citation35	Hosp. rate (x100,000)^Citation32 ^, ^Citation36	Hosp. rate (%)^Citation32 ^, ^Citation36	Case fatality ratio (%)^Citation36	GP consult. rate (%)^Citation37 ^, ^Citation38	GP consult. rate (x100,000)^Citation37 ^, ^Citation38	GP consult. rate (x100,000)^Citation39 ^, ^Citation40	Adjustment factor for total AOM cases^Citation39	Hosp. rate (x100,000)^Citation7 ^, ^Citation37
<1	4.31	9.2	20.4	4.31*	2.6	550	7.1	0	92.9	7,154	16,482.1	1.2	288.0
1	1.48	12.9	20.4	3.62	1.7	550	7.1	0	92.9	7,154	22,517.9	1.2	288.0
2	1.48	17.1	20.4	3.62	2.9	550	7.1	0	92.9	7,154	18,455.4	1.2	133.1
3	1.48	17.1	20.4	3.62	2.9	550	7.1	0	92.9	7,154	25,767.9	1.2	185.9
4	1.48	17.1	20.4	3.62	2.9	550	7.1	0	92.9	7,154	19,267.9	1.2	139.0
5–9	0.60	4.8	20.4	0.90	0	121	7.1	0	92.9	1,570	10,869.2	2.7	78.4
10–14	0.00	4.8	20.4	0.09	0	121	7.1	0	92.9	1,570	2,470.5	4.1	17.8
15–18	0.15	11.5	44.4	0.07	0	58	2.6	4	97.4	2,155	740.5	2.3	5.3
Corrected OVE for post-PCV-7 epidemiology
			vs. IPD		vs. CAP (hospitalizations)		vs. CAP (GP visits)				vs. any AOM
PCV-7			0		0		0				0
PHiD-CV			40		3		3				24
PCV-13			40		3		3				21
No vaccination			-100		-26		-4				-10

* Refers to 1 month-1 y age.

AOM: Acute otitis media; CAP: Community-acquired pneumonia; CFR: Case fatality rate; Consult.: Consultation; GP: General practitioner; Hosp.: Hospitalization; IPD: Invasive pneumococcal disease.

Table 3. Disutilities used in the model.

Short term	Estimate	Source
Meningitis (in-patient)	0.023	^Citation45
Bacteremia (in-patient)	0.008	^Citation45
Bacteremia (out-patient)	0.008	As above
Pneumonia (in-patient)	0.008	As above
Pneumonia (out-patient)	0.006	^Citation45
AOM (out-patient)	0.005	^Citation46
AOM/TTP hospitalized	0.005	As above
AOM complications	0.005	As above
Long term	Estimate	Source
Neurological sequelae meningitis	0.400	^Citation47
Hearing loss from meningitis	0.200	^Citation47 ^, ^Citation48
Meningitis long-term sequelae children	0.269	Calculated in model
Meningitis long-term sequelae adults	0.286	Calculated in model
Bacteremia long-term sequelae children	0.269	As meningitis children
Bacteremia long-term sequelae adults	0.286	As meningitis adults
Hearing loss from AOM	0.090	^Citation49
AOM long-term sequelae	0.090	As above

AOM: Acute otitis media; TTP: Tympanostomy tube placement.

Table 4. Direct costs estimated in the model.

	Unit cost (€)	Source
PHiD-CV	47.73	Parity price with PCV-13
PCV-13	47.73	Maximum price for NHS^Citation50 ^, ^Citation51
Meningitis - first year (acute episode)	8,067	DRG 560 tariff^Citation52
Bacteremia - hospitalized	3,176	DRG 417 tariff^Citation52
Pneumonia - hospitalized	1,948	DRG 91 tariff^Citation52
AOM hospitalized	662	DRG 70 tariff^Citation52
Pneumonia - outpatient	97	^Citation53
AOM GP consultations	76	^Citation53
Neurological sequelae (per year)	11,249	^Citation35
Hearing loss (per year)	866	^Citation35

AOM: Acute otitis media; DRG: Diagnosis-related group; GP: General practitioner; NHS: National Health Service; PCV-13: 13-valent pneumococcal conjugate vaccine; PHiD-CV: pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine.

Istituto Superiore di Sanita . Dati di sorveglianza delle malattie batteriche invasive aggiornati al 12 agosto 2015. 2015 [accessed 2015 Dec 22]. http://www.iss.it/binary/mabi/cont/Report_MBI_20150812_V5.pdf

 Google Scholar

Health Protection Agency (HPA) . Pneumococcal serotype distribution for samples referred for serotyping epidemiological years (July–June): 2000/1 to 2005/6. 2009 [accessed 2015 Dec 22]. http://webarchivenationalarchivesgov.uk/20100304045635/http://wwwhpaorguk/webw/HPAweb&HPAwebStandard/HPAweb_C/1195733824984?p=1203409671918

 Google Scholar

ISTAT - Istituto Nazionale di Statistica . Popolazione residente in Italia al 1° Gennaio 2015 per età, sesso e stato civile. 2015 [accessed 2015 Dec 22]. http://demo.istat.it/pop2015/index.html

 Google Scholar

Baldo V , Cocchio S , Baldovin T , Buja A , Furlan P , Bertoncello C , Russo F , Saia M . A population-based study on the impact of hospitalization for pneumonia in different age groups. BMC Infect Dis 2014; 14:485; PMID:25192701; https://doi.org/10.1186/1471-2334-14-485

 PubMed Web of Science ®Google Scholar

Pedianet . Report Dati Pedianet Anno 2006. http://www.pedianet.it/bin=1039/Report-2006.pdf, 2006

 Google Scholar

Sterrantino C , Trifirò G , Lapi F , Pasqua A , Mazzaglia G , Piccinni C , Cricelli C , Rossi A , Blasi F . Burden of community-acquired pneumonia in Italian general practice. Eur Respiratory J 2013; 42:1739-42; PMID:23949958; https://doi.org/10.1183/09031936.00128713

 PubMed Web of Science ®Google Scholar

Liese J , Silfverdal S , Giaquinto C , Carmona A , Larcombe J , Garcia-Sicilia J , Fuat A , Garces-Sanchez M , Basanta ML , Hiraldo EM , et al. Incidence and clinical presentation of acute otitis media in children aged <6 years in European medical practices. Epidemiol Infect 2014; 142:1778-88; PMID:24330917; https://doi.org/10.1017/S0950268813002744

 PubMed Web of Science ®Google Scholar

Marchisio P , Cantarutti L , Sturkenboom M , Girotto S , Picelli G , Dona D , Scamarcia A , Villa M , Giaquinto C . Burden of acute otitis media in primary care pediatrics in Italy: a secondary data analysis from the Pedianet database. BMC Pediatrics 2012; 12:1-8; PMID:22208358; https://doi.org/10.1186/1471-2431-12-185

 PubMed Web of Science ®Google Scholar

Ansaldi F , Sticchi L , Durando P , Carloni R , Oreste P , Vercelli M , Crovari P , Icardi G . Decline in pneumonia and acute Otitis Media after the Introduction of childhood Pneumococcal vaccination in Liguria, Italy. J Int Med Res 2008; 36:1255-60; PMID:19094434; https://doi.org/10.1177/147323000803600612

 PubMed Web of Science ®Google Scholar

Bennett JE , Sumner W, II , Downs SM , Jaffe DM . Parents' utilities for outcomes of occult bacteremia. Arch Pediatrics Adolescent Med 2000; 154:43-8

 PubMedGoogle Scholar

Oh PI , Maerov P , Pritchard D , Knowles SR , Einarson TR , Shear NH . A cost-utility analysis of second-line antibiotics in the treatment of acute otitis media in children. Clin Therapeutics 1996; 18:160-82; PMID:8851461; https://doi.org/10.1016/S0149-2918(96)80188-3

 PubMed Web of Science ®Google Scholar

Morrow A , De Wals P , Petit G , Guay M , Erickson LJ . The burden of pneumococcal disease in the Canadian population before routine use of the seven-valent pneumococcal conjugate vaccine. Can J Infect Dis Med Microbiol 2007; 18:121-7; PMID:18923713

 PubMed Web of Science ®Google Scholar

Cheng AK , Niparko JK . Cost-utility of the cochlear implant in adults: A meta-analysis. Arch Otolaryngol Head Neck Surg 1999; 125:1214-8; https://doi.org/10.1001/archotol.125.11.1214

 PubMed Web of Science ®Google Scholar

Oostenbrink R , Oostenbrink JB , Moons KGM , Derksen-Lubsen G , Essink-Bot ML , Grobbee DE , Redekop WK , Moll HA . Cost-utility analysis of patient care in children with meningeal signs. Int J Technol Assessment Health Care 2002; 18:485-96; PMID:12391942

 PubMed Web of Science ®Google Scholar

Decreto-Legge 8 luglio 1974, n. 264 - Norme per l'estinzione dei 760 debiti degli enti mutualistici nei confronti degli enti ospedalieri, il finanziamento della spesa ospedaliera e l'avvio della riforma sanitaria. (GU n.181 del 11-7-1974) Decreto-Legge convertito con modificazioni dalla L. 17 agosto 1974, n. 386 (in G.U. 29/08/1974, n.225). 1976 [accessed 2016 Jan 15]. http://www.normattiva.it/atto/caricaDettaglioAtto?atto.dataPubblicazioneGazzettaD1974-07-11&attocodiceRedazionaleD074U0264&currentPageD1

 Google Scholar

Federazione nazionale unitaria titolari di farmacia . Prevenar 13. 2016 [accessed 2016 Jan 15]. http://www.federfarma.it/Farmaci-e-farmacie/Cerca-un-farmaco

 Google Scholar

Ministero della Salute . Remunerazione prestazioni di assistenza ospedaliera per acuti, assistenza ospedaliera di riabilitazione e di lungodegenza post acuzie e di assistenza specialistica ambulatoriale. Gazzetta Ufficiale Serie Generale 2013; 23. http://www.gazzettaufficiale.it/do/gazzetta/serie_generale/3/pdfPaginato?dataPubblicazioneGazzetta=20130128&numeroGazzetta=23&tipoSerie=SG&tipoSupplemento=GU&numeroSupplemento=0&numPagina=1&edizione=0

 Google Scholar

Mantovani LG , de Portu S , Cortesi PA , Belisari A . Valutazione economica del vaccino coniugato 13-valente. Italian J Public Health 2010; 7:36-45

 Google Scholar